Mechanism of KDM5C-Mediated H3K4me3 Demethylation of HOXC-AS3 in the Proliferation of Colorectal Cancer Cells

Abstract

Colorectal cancer (CRC) ranks as the third most prevalent malignancy and the second leading cause of cancer-related mortality worldwide. This study explored the role of lysine-specific histone demethylase 5C (KDM5C) in CRC progression. Expression levels of KDM5C, HOXC-AS3, and discs large MAGUK scaffold protein 4 (DLG4) were evaluated. Following the KDM5C knockdown, cell proliferation assays were conducted. The recruitment of KDM5C and histone H3 lysine 4 tri-methylation (H3K4me3) to the HOXC-AS3 promoter region was investigated. Furthermore, the subcellular distribution of HOXC-AS3 was assessed using nuclear-cytoplasmic fractionation and RNA fluorescence in situ hybridization (RNA-FISH). The interactions between HOXC-AS3, YTH domain-containing protein 1 (YTHDC1), and DLG4 were detected. The stability of DLG4 mRNA was evaluated, and the functional roles of HOXC-AS3 and DLG4 in CRC cells were examined through combined experimental analyses. KDM5C expression was elevated in CRC cells, whereas HOXC-AS3 and DLG4 levels were notably reduced. Silencing KDM5C resulted in suppressed cell proliferation. Mechanistically, KDM5C inhibited HOXC-AS3 expression by demethylating H3K4me3 at its promoter. HOXC-AS3 promoted DLG4 mRNA stability by recruiting the RNA-binding protein YTHDC1. Combined experimental results indicated that overexpression of HOXC-AS3 or DLG4 reduced the inhibitory effect of KDM5C downregulation on CRC cells. In conclusion, KDM5C promotes CRC cell proliferation by demethylating H3K4me3, repressing HOXC-AS3 expression. The reduced HOXC-AS3 levels impair the recruitment of YTHDC1, leading to decreased DLG4 expression.

Keywords: DLG4; HOXC‐AS3; KDM5C; YTHDC1; colorectal cancer.